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Ai-Hua Zhang,1 Guang-Xia Dai,2 Qi-Dong Zhang,1 Hong-Dong Huang,1 Wen-Hu Liu1 1Nephrology Department, Capital Medical University Affiliated Beijing Friendship Hospital, Beijing, People’s Republic of China; 2Endocrinology Department, Beijing Nanyuan Hospital, Beijing, People’s Republic of ChinaCorrespondence: Hong-Dong Huang; Wen-Hu Liu, Nephrology Department, Capital Medical University Affiliated Beijing Friendship Hospital, No. 95 Yong An Road, Xi Cheng District, Beijing, 100050, People’s Republic of China, Tel +86-10 63138579, Fax +86-10 63139144, Email huangHD201902@163.com; l13901163354@163.comBackground: Primary membranous nephropathy (PMN) is a common cause of nephrotic syndrome in adults. Forty percent of the patients continue to progress and eventually develop into chronic renal failure. Although phospholipase A2 receptor (PLA2R) is the major antigen of PMN, the clinical features do not often parallel with the antibody titers. Therefore, it is significant to find relative credible markers to predict the treatment response.Methods: One hundred and eighteen PMN patients were recruited. The response to treatment was defined as ALB≥ 30g/L at 6 months and complete remission (CR) or not at the end of the follow-up. Renal outcome endpoint was defined as 50% or more Cr increase at the end.Results: The patients with poor treatment effects had numerically higher platelet-lymphocytes ratio (PLR). For patients with CR or not, the difference was near to statistic significant (P=0.095). When analyzing CR or not, the fitting of the binary logistic regression model including both PLA2R Ab titer and PLR (Hosmer–Lemeshow test: χ2=8.328, P = 0.402; OR (PLA2R Ab titer) = 1.002 (95% CI 1.000– 1.004, P = 0.042); OR (PLR) = 1.006 (95% CI 0.999– 1.013, P = 0.098)) was markedly better than that with only PLA2R Ab titer (Hosmer–Lemeshow test: χ2=13.885, P = 0.016). The patients with renal function deterioration showed significantly higher monocyte-lymphocyte ratio (MLR) (0.26 (0.22– 0.31) vs 0.18 (0.13– 0.22), P = 0.012).Conclusion: PMN patients with poor treatment response tended to have higher PLR at the time of renal biopsy, and a higher MLR was associated with poor renal outcomes. Our findings suggested that PLR and MLR might be used to predict treatment efficacy and prognosis for PMN patients, respectively.Keywords: membranous nephropathy, peripheral blood cell ratios, platelet-lymphocytes ratio, monocyte–lymphocyte ratio, treatment response, outcome

Introduction: Apoptosis of vascular smooth muscle cells induced by hyperphosphatemia is a critical mechanism of chronic kidney disease-related vascular disorders. The present study investigated whether extracellular calcium-sensing receptor (CaSR) regulates stanniocalcin 2 (STC2) expression in HAoSMCs and subsequently protects HAoSMCs from high-phosphate-induced apoptosis. Methods: HAoSMCs were cultured, and STC2 expression was determined by qPCR. A calcimimetic (NPS R-568) or calcilytic (NPS-2143) was applied to HAoSMCs. STC2 mRNA and protein levels were measured by qPCR and Western blot, respectively, and confocal microscopy was employed to investigate subcellular localization. STC2 overexpression and silencing were induced to assess the effects of STC2 on high-phosphate-induced apoptosis, which was determined by caspase-3 levels and TUNEL staining. The anti-apoptotic effect of CaSR-induced STC2 was confirmed by interfering with STC2 expression in the presence of NPS R-568. Results: The constitutive expression of STC2 was confirmed. STC2 mRNA and protein levels were increased by NPS R-568 with or without high phosphate. NPS-2143 resulted in decreased STC2 mRNA levels, but decreased STC2 protein levels were only found under the high-phosphate condition. Confocal microscopy demonstrated the colocalization of STC2 and plasma membrane or endoplasmic reticulum markers. STC2 overexpression reduced HAoSMCs apoptosis, which were reversed with STC2 silencing. NPS R-568 treatment reduced HAoSMCs apoptosis, but STC2 silencing abolished the protective effect. Conclusion: This is the first evidence that STC2 is regulated by CaSR in HAoSMCs. CaSR activation-induced STC2 has putative anti-apoptotic effects against high phosphate. Calcimimetics are promising agents to treat uremic vascular injury.

Mitochondrial dysfunction in proximal tubular epithelial cells is a key event in acute kidney injury (AKI), which is a risk factor for the development of chronic kidney disease (CKD). Apelin is a bioactive peptide that protects against AKI by alleviating inflammation, inhibiting apoptosis, and preventing lipid oxidation, but its role in protecting against mitochondrial damage remains unknown. Herein, we examined the protective effects of apelin on mitochondria in cisplatin-stimulated human renal proximal tubular epithelial cells and evaluated its therapeutic efficacy in cisplatin-induced AKI mice. In vitro, apelin inhibited the cisplatin-induced mitochondrial fission factor (MFF) upregulation and the fusion-promoting protein optic atrophy 1 (OPA1) downregulation. Apelin co-treatment reversed the decreased levels of the deacetylase, Sirt3, and the increased levels of protein acetylation in mitochondria of cisplatin-stimulated cells. Overall, apelin improved the mitochondrial morphology and membrane potential in vitro. In the AKI model, apelin administration significantly attenuated mitochondrial damage, as evidenced by longer mitochondrial profiles and increased ATP levels in the renal cortex. Suppression of MFF expression, and maintenance of Sirt3 and OPA1 expression in apelin-treated AKI mice was also observed. Finally, exogenous administration of apelin normalized the serum level of creatinine and urea nitrogen and the urine levels of NGAL and Kim-1. We also confirmed a regulatory pathway that drives mitochondrial homeostasis including PGC-1α, ERRα and Sirt3. In conclusion, we demonstrated that apelin ameliorates renal functions by protecting tubular mitochondria through Sirt3 upregulation, which is a novel protective mechanism of apelin in AKI. These results suggest that apelin has potential renoprotective effects and may be an effective agent for AKI treatment to significantly retard CKD progression.

// Xue-Min Wu 1,* , Zhi-Feng Xi 2,* , Pinhu Liao 3,* , Hong-Dong Huang 4,* , Xiao-Ying Huang 1,* , Chao Wang 3,* , Yun Ma 5 , Qiang Xia 2 , Jin-Guang Yao 1 and Xi-Dai Long 1,2 1 Department of Pathology, The Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, China 2 Department of Liver Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China 3 Department of Medicine, The Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, China 4 Division of Medicine, Beijing Shijitan Hospital, Capital Medical University, Beijing, China 5 Department of Pathology, The Affiliated Tumor Hospital, Guangxi Medical University, Nanning, China * These authors have contributed equally to the manuscript Correspondence to: Xi-Dai Long, email: // Keywords : microRNA-4651, aflatoxin B1, hepatocellular carcinoma, diagnostic and prognostic biomarkers Received : November 22, 2016 Accepted : February 18, 2017 Published : March 08, 2017 Abstract Background: The serum microRNAs have been reported as potential biomarkers for hepatitis virus-related hepatocellular carcinoma (HCC); however, their role in aflatoxin B1 (AFB1)-related HCC to has not yet been evaluated. Materials and Methods: We conducted a case-control study, including 366 HCC cases and 662 controls without any evidence of tumors, to identify and assess diagnostic and prognostic potential of serum microRNAs for AFB1-related HCC. The sensitivity, specificity, and area under the receiver operating characteristic curve (AUC) were used to elucidate diagnostic performance, and to compare the microRNAs with α-fetoprotein (AFP) at a cutoff of 20 ng/mL (AFP20) and 400 ng/mL (AFP400). Results: We found 8 differentially expressed microRNAs via the microRNA array analysis; however, only microRNA-4651 was further identified to detect AFB1-positive HCC but not AFB1-negative HCC. For AFB1-positive HCC, microRNA-4651 showed higher accuracy and sensitivity than AFP400 (AUC, 0.85 vs . 0.72; Sensitivity, 78.1% vs. 43.0%). Compared to AFP20, microRNA-4651 exhibited higher potential in identifying small-size (0.68 vs. 0.84 for AUC and 36.7% vs . 75.5% for sensitivity, respectively) and early-stage HCC (0.69 vs . 0.84 for AUC and 38.7% vs . 75.7% for sensitivity, respectively). Additionally, miR-4651 was also associated with HCC prognosis (hazard risk value, 2.67 for overall survival and 3.62 for tumor recurrence analysis). Conclusions: These data suggest that serum microRNA-4651 may be a useful marker for HCC diagnosis and prognosis, especially AFB1-positive cases.

Podocytes are specialized cells that contribute critically to the normal structure and function of the glomerular filtration barrier. Their depletion plays an important role in the pathogenesis of glomerulosclerosis. Here, we report generation of a genetic model of conditional podocyte ablation and regeneration in zebrafish using a bacterial nitroreductase strategy to convert a prodrug, metronidazole, into a cytotoxic metabolite. A transgenic zebrafish line was generated that expresses green fluorescence protein (GFP) and the nitroreductase fusion protein under the control of the podocin promoter Tg (podocin:nitroreductase–GFP) . Treatment of these transgenic zebrafish with metronidazole results in podocyte apoptosis, a loss of nephrin and podocin expression, foot process effacement, and a leaky glomerular filtration barrier. Following metronidazole washout, proliferating cells were detected in the glomeruli of recovering transgenic fish with a restoration of nitroreductase–GFP fluorescence, nephrin and podocin expression, a reestablishment of normal foot process architecture, and glomerular barrier function. Thus, our studies show that zebrafish podocytes are capable of regenerating following depletion, and establish the Tg (podocin:NTR–GFP) fish as a new model to study podocyte injury and repair.

In hepatocellular carcinoma (HCC), hotspot mutation in codon 249 of the p53 gene has been associated with exposure to aflatoxin B1 (AFB1). While the polymorphism of DNA repair gene X-ray repair cross-complementary group 1 (XRCC1) Arg399Gln may be related with AFB1-DNA adducts and gene mutations. Five hundred one HCCs were included in this study to investigate the role of the XRCC1 codon 399 polymorphism on hotspot mutation in codon 249 of the p53 gene. The genotypes of XRCC1 codon 399 and p53 codon 249 were examined by PCR-RFLP. The HCC patients with XRCC1 genotypes with 399 Gln (namely: XRCC1-AG/GG) exhibited a significantly higher frequency of the p53 hotspot mutations in codon 249 than those with the wild-type homozygote of XRCC1 [namely: XRCC1-AA, adjusted odds ratio (OR) = 6.77, 95% confidence interval (CI) = 4.34–10.57]. Compared with those individuals who did express XRCC1-AA as reference (OR = 1), moreover, individuals featuring XRCC1-AG/GG and AFB1-DNA adducts did experience a significantly greater frequency of the hotspot mutation in codon 249 of the p53 gene (adjusted OR = 28.37, 95% CI = 13.19–61.02, P

To investigate whether house dust mite (HDM) could induce CD(4)(+) CD(25)(+) T cells infiltration into asthmatic airways in patients vivo.Ten subjects with asthma underwent initial bronchoscopy during which normal saline and HDM were administered to two sublobar segments separately. The second bronchoscopy were carried out and bronchoal lavage fluid from HDM-challenged sites and saline-challenged sites were separately taken 24 h later. The differential cell counts were determined, and the absolute number of each type was calculated. At the same time, CD(3)(+), CD(4)(+) and CD(4)(+) CD(25)(+) T cells were determined by flow-cytometric analysis. We compared cellular counts in airways without and after topical instillation of HDM.Eosinophile granulocyte cells of broncho-alveolar fluid in the HDM-challenged sites (1.4 +/- 0.1) x 10(6)/ml are more than it in control sites (0.3 +/- 0.1) x 10(6)/ml, P0.003. Lymphocyte cells of BALF in the HDM-challenged sites (2.2 +/- 0.3) x 10(6)/ml are more than it in control sites (0.3 +/- 0.1) x 10(6)/ml, P0.001; CD(4)(+) CD(25)(+)T cells of BALF in the HDM-challenged sites (784.0 +/- 281.3) cell/microl are more than it in control sites (7.7 +/- 3.6) cell/microl, P0.001.Our findings suggest that HDM is capable of inducing CD(4)(+) CD(25)(+) T cells recruitment into non-acute mild allergic asthmatic airways.

In hepatocellular carcinoma (HCC), hotspot mutation in codon 249 of the p53 gene has been associated with exposure to aflatoxin B1 (AFB1). While the polymorphism of DNA repair gene X-ray repair cross-complementary group 1 (XRCC1) Arg399Gln may be related with AFB1-DNA adducts and gene mutations. Five hundred one HCCs were included in this study to investigate the role of the XRCC1 codon 399 polymorphism on hotspot mutation in codon 249 of the p53 gene. The genotypes of XRCC1 codon 399 and p53 codon 249 were examined by PCR-RFLP. The HCC patients with XRCC1 genotypes with 399 Gln (namely: XRCC1-AG/GG) exhibited a significantly higher frequency of the p53 hotspot mutations in codon 249 than those with the wild-type homozygote of XRCC1 [namely: XRCC1-AA, adjusted odds ratio (OR) = 6.77, 95% confidence interval (CI) = 4.34-10.57]. Compared with those individuals who did express XRCC1-AA as reference (OR = 1), moreover, individuals featuring XRCC1-AG/GG and AFB1-DNA adducts did experience a significantly greater frequency of the hotspot mutation in codon 249 of the p53 gene (adjusted OR = 28.37, 95% CI = 13.19-61.02, P0.01). This study suggests that the XRCC1 Arg399Gln polymorphism and AFB1-DNA adducts are associated with the increased frequency of the p53 mutations in codon 249.